Zaitsev Sergei, Sharma Hari Shanker, Sharma Aruna, Manzhulo Igor, Polevshchikov Alexander, Kudriavtsev Igor, Khotimchenko Yuri, Pak Oleg, Bryukhovetskiy Andrey, Bryukhovetskiy Igor
Department of Fundamental Medicine, School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia.
International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, University Hospital, Uppsala University, S-75185 Uppsala, Sweden.
Int Rev Neurobiol. 2020;151:253-279. doi: 10.1016/bs.irn.2020.03.027. Epub 2020 May 13.
Glioblastoma multiforme (GBM) is one of the most aggressive human brain tumors. The prognosis is unfavorable with a median survival of 15 months. GBM aggressive nature is associated with a special phenotype of cancer cells that develops because of the transforming growth factor β (TGF-β). The study was aimed at providing experimental justification in vivo of a possibility to suppress TGF-β production in a tumor via pro-inflammatory modification of cancer cell microenvironment, using CD45+ mononuclear cells of the red bone marrow.
The experiment used animals with transplanted C6 glioma. The animals were divided into 4 groups: (I) control (N=60); (II) group of rats (N=30) that received granulocyte colony-stimulating factor (G-CSF) to recruit CD45+ bone marrow mononuclear cells into their systemic circulation (G-CSF group); (III) group of rats (N=30) that received pro-inflammatory therapy to trigger systemic inflammatory reaction by injecting bacterial lipopolysaccharides (LPS) and interferon-γ (IFNγ); (IV) rats (N=30), stimulated with G-CSF, followed by pro-inflammatory therapy. Stereotaxic modeling of a brain tumor in experimental animals, as well as a combination of morphological, immunocytochemical analyses and immunosorbent assay were used.
TGF-β1 production in the tumor tissue resulted being inversely proportional to the intensity of proliferation processes and directly proportional to the size of necrosis areas, peaking on the 28th day of the experiment. Stimulation of experimental animals with G-CSF recruits CD45+ mononuclear stem and progenitor cells into the systemic circulation of experimental animals with C6 glioma, accompanied by intensification of microglial proliferation in the tumor and infiltration of the tumor tissue with microglial cells. Pro-inflammatory therapy against G-CSF stimulation results in polarization of microglia/macrophages population together with intensified antigen presentation, lower production of TGF-β and IL10, increased synthesis of pro-inflammatory cytokines TNFα and IL1 in the tumor lesion and adjacent brain matter, remodeling of tumor matrix and higher survival rates for the experimental animals.
Pro-inflammatory inflammatory modification of cancer cell microenvironment suppresses TGFβ production in a tumor and increases survival rates of the rats with transplanted poorly differentiated malignant brain glioma.
多形性胶质母细胞瘤（GBM）是最具侵袭性的人类脑肿瘤之一。其预后不佳，中位生存期为15个月。GBM的侵袭性与因转化生长因子β（TGF-β）而产生的癌细胞特殊表型有关。本研究旨在通过使用红骨髓的CD45 + 单核细胞对癌细胞微环境进行促炎性修饰，在体内为抑制肿瘤中TGF-β产生的可能性提供实验依据。
实验使用移植了C6胶质瘤的动物。动物分为4组：（I）对照组（N = 60）；（II）接受粒细胞集落刺激因子（G-CSF）以将CD45 + 骨髓单核细胞募集到其体循环中的大鼠组（N = 30）（G-CSF组）；（III）通过注射细菌脂多糖（LPS）和干扰素-γ（IFNγ）接受促炎治疗以引发全身炎症反应的大鼠组（N = 30）；（IV）先用G-CSF刺激，然后进行促炎治疗的大鼠（N = 30）。使用实验动物脑肿瘤的立体定向建模以及形态学、免疫细胞化学分析和免疫吸附测定的组合。
肿瘤组织中TGF-β1的产生与增殖过程的强度成反比，与坏死区域的大小成正比，在实验的第28天达到峰值。用G-CSF刺激实验动物会将CD45 + 单核干细胞和祖细胞募集到患有C6胶质瘤的实验动物的体循环中，伴随着肿瘤中小胶质细胞增殖的加剧以及肿瘤组织被小胶质细胞浸润。针对G-CSF刺激的促炎治疗导致小胶质细胞/巨噬细胞群体极化，同时抗原呈递增强，TGF-β和IL10的产生降低，肿瘤病变和相邻脑实质中促炎细胞因子TNFα和IL1的合成增加，肿瘤基质重塑，实验动物的存活率提高。
癌细胞微环境的促炎性修饰可抑制肿瘤中TGFβ的产生，并提高移植了低分化恶性脑胶质瘤大鼠的存活率。
